Diagnosis and treatments relating to her3 inhibitors
An inhibitor, cancer technology, applied in chemical instruments and methods, anti-animal/human immunoglobulins, instruments, etc., can solve problems such as proving survival advantage
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Embodiment 4
[0259] Example 4 provides an assay for determining the distribution of NRG1 expression in a patient population. In one embodiment, a bivariate Gaussian distribution is used to estimate the inflection point between overexpression of NRG1 and lack of overexpression of NRG1.
[0260] An example of a cancer exhibiting a bimodal NRG1 expression profile shown herein is head and neck squamous cell carcinoma (HNSCC). As discussed in Example 4, the HNSCC cancer population exhibited a Gaussian bimodal distribution profile of cancers with NRG1 overexpression and cancers lacking NRG1 overexpression. The distribution analysis provided an inflection point of approximately 0.3689 on the logarithmic scale, corresponding to approximately 1.50 on the linear scale.
[0261] In one embodiment, the cancer overexpressing NRG1 also exhibits neuregulin-induced autocrine signaling. Cancers exhibiting neuregulin-induced autocrine signaling can be identified by the presence of NRG1 and HER3 co-express...
Embodiment 1
[0360] MEHD7945A specific for both HER3 and EGFR
[0361] MEHD7945A (also known as DL11f) is an antibody comprising an antigen-binding domain with binding specificity for both EGFR and HER3. WO 2010 / 108127 and Schaefer et al., Cancer Cell, 20:472-486 (2011). Typically, dual targeting agents are constructed by linking two different antigen-binding assays, each module capable of binding only one antigen. In contrast, in MEHD7945A, each module (Fab) can bind either of the two antigens, thus having the potential to elicit enhanced binding affinity from affinity effects. To confirm that each of the two identical Fabs of MEHD7945A could bind EGFR or HER3, a competitive binding assay was performed. As the content of EGFR-ECD increased, the binding of MEHD7945A to immobilized HER3-ECD was reduced in a dose-dependent manner. In contrast, the binding of MEHD7945A to immobilized EGFR-ECD was competed by soluble HER3-ECD protein. As expected, given their relative binding constants, hi...
Embodiment 2
[0363] MEHD7945A inhibits EGFR and HER2 / HER3-dependent signaling
[0364] The dual activity of MEHD7945A in a cell signaling assay was determined. To evaluate the inhibitory function against HER3, MCF-7 cells in which the HER2 / HER3 pathway was effectively activated were treated with NRG. Before NRG stimulation, treatment with MEHD7945A potently inhibited HER3 phosphorylation in a dose-dependent manner, and significantly decreased AKT and ERK1 / 2 phosphorylation ( figure 2 A). MEHD7945A inhibits the phosphorylation of HER3 with an IC50 of 0.05 μg / ml, the phosphorylation of AKT with an IC50 of 0.19 μg / ml, and the phosphorylation of ERK1 / 2 with an IC50 of 1.13 μg / ml. Similar results were obtained with anti-HER3 treatment using a monospecific antibody against HER3 with comparable HER3 binding affinity. Anti-HER3 inhibited the phosphorylation of HER3 with an IC50 of 0.12 μg / ml, the phosphorylation of AKT with an IC50 of 0.74 μg / ml, and the phosphorylation of ERK1 / 2 with an IC50 ...
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